The goal of this project is to understand how retroviruses adversely affect the central nervous system. We are utilizing mouse retroviruses which cause rapid non-inflammatory neurodegeneration and have used this system to study interactions between virus and brain. Viral protein involved in neuroinvasiveness: We previously found that an accessory viral protein glycosylated gag was involved in spread of virus to the brain. Expression of this protein has now been found to be required for dissemination of virus from their initial sites of replication in spleen and bone marrow to extrahematopoietic organs such as liver, gut, exocrine glands, reproductive organs as well as brain. During studies of protein trafficking we found that a processed form of glycosylated gag is incorporated into virions. This form exists as a Type II integral membrane protein, is expressed at the plasma membrane, is acylated with palmitic acid and appears to recycle from the cell membrane to the Golgi Apparatus.. Importance of microglial cell infection in retroviral neurovirulence. Two chimeric murine retroviruses, which utilize the same receptor but differ in their envelope sequences have been shown to infect the brain, and appear also to infect primarily microglial cells in the brain. After intraperitoneal inoculation, one of these viruses causes a fatal neurologic disease, the other appears avirulent. Studies of viral burden revealed that, although these two viruses were equally efficient at gaining initial access to the brain from the periphery, neurovirulence was associated with enhanced efficiency of virus spread to microglial cells within the brain and that this phenotype was determined by the sequence of the viral envelope gene.